Related Experiment Video
Updated: Oct 2, 2025
Advances in Human Induced Pluripotent Stem Cell-Derived Chimeric Antigen Receptor-Expressing Natural Killer Cells
Published on: February 14, 2025
A chimeric switch-receptor PD1-DAP10-41BB augments NK92-cell activation and killing for human lung Cancer H1299 Cell
Lingtong Zhi1, Meichen Yin1, Xin Su1
1Synthetic Biology Engineering Lab of Henan Province, School of Life Sciences and Technology, Xinxiang Medical University, Xinxiang, Henan Province, PR China.
Abstract:
Engineered natural killer (NK) cell-based therapies have been potentially broadly applicable and exhibited promising results in clinical trials, particularly in the fight against cancers. NK cell immunotherapy however always remains variable. One major obstacle is the inhibitory pathway including PD1/PDL1, providing tumor cells an escape mechanism from immunosurveillance. In this regard, we rationally designed a chimeric switch-receptor (CSR) PD1-DAP10-41BB, which comprising the ectodomain of PD1 fused to the co-stimulatory receptor DAP10 and 41BB. Therefore, by exchanging the transmembrane and cytoplasmic tail of PD1 with positive costimulatory molecules DAP10 and 41BB signaling domains, the negative PD1/PDL1 signal pathway was thus converted into a positive one. This CSR-expressing NK92 cells showed a typical parental NK92 phenotype and improved cytotoxicity against human lung cancer H1299 cells. Besides, the expression of CSR elicited a significant increase of effector molecules such as perforin and granzymes, which can induce apoptosis of H1299 cells. More importantly, in the solid tumor cell H1299-bearing mice model, the CSR-modified NK92 cells significantly inhibited tumor growth. Collectively, we demonstrated that expression of PD1-DAP10-41BB augmented NK92-cell activation and killing in vitro and in vivo, which provides a considerable avenue of using NK-tailored chimeric receptor engineered NK92 cells to treat a wide range of solid tumors.
Insights
Engineered NK cells with a novel chimeric switch-receptor (CSR) targeting the PD1/PDL1 pathway demonstrated enhanced cancer-killing ability. This immunotherapy approach significantly inhibited solid tumor growth in preclinical models.
Area of Science:
- Immunology
- Cancer Therapy
- Cell Engineering
Background:
- Natural killer (NK) cell immunotherapy shows promise for cancer treatment but faces challenges with tumor immune evasion via inhibitory pathways like PD1/PDL1.
- Tumor cells exploit the PD1/PDL1 pathway to escape NK cell-mediated immunosurveillance, limiting therapeutic efficacy.
Purpose of the Study:
- To engineer NK cells with a chimeric switch-receptor (CSR) that converts the inhibitory PD1/PDL1 signal into a co-stimulatory signal.
- To evaluate the efficacy of CSR-engineered NK92 cells in enhancing anti-tumor activity against lung cancer both in vitro and in vivo.
Main Methods:
- A chimeric switch-receptor (CSR) PD1-DAP10-41BB was designed, fusing the PD1 ectodomain with DAP10 and 41BB co-stimulatory signaling domains.
- NK92 cells were engineered to express the CSR.
- Cytotoxicity assays, effector molecule analysis (perforin, granzymes), and in vivo tumor growth inhibition studies in a H1299 lung cancer mouse model were performed.
Main Results:
- CSR-expressing NK92 cells maintained a typical NK92 phenotype but exhibited significantly improved cytotoxicity against H1299 lung cancer cells.
- Expression of the CSR led to increased levels of effector molecules like perforin and granzymes, promoting cancer cell apoptosis.
- CSR-modified NK92 cells significantly inhibited tumor growth in a solid tumor mouse model.
Conclusions:
- The PD1-DAP10-41BB CSR effectively converts an inhibitory signal into a co-stimulatory one, augmenting NK92 cell activation and cytotoxic function.
- Engineered NK92 cells expressing the PD1-DAP10-41BB CSR represent a promising strategy for enhancing cancer immunotherapy, particularly against solid tumors.
- This NK-tailored chimeric receptor engineering approach offers a viable avenue for treating various solid tumors.
